U.S. patent application number 10/809754 was filed with the patent office on 2004-12-09 for process for preparing a pharmaceutical active ingredient with high specific surface area.
Invention is credited to Samburski, Guy.
Application Number | 20040247689 10/809754 |
Document ID | / |
Family ID | 33131747 |
Filed Date | 2004-12-09 |
United States Patent
Application |
20040247689 |
Kind Code |
A1 |
Samburski, Guy |
December 9, 2004 |
Process for preparing a pharmaceutical active ingredient with high
specific surface area
Abstract
Provided is a process for micronization of active pharmaceutical
ingredients to provide active pharmaceutical ingredients with a
high specific surface area.
Inventors: |
Samburski, Guy;
(Ganot-Hadar, IL) |
Correspondence
Address: |
KENYON & KENYON
One Broadway
New York
NY
10004-1050
US
|
Family ID: |
33131747 |
Appl. No.: |
10/809754 |
Filed: |
March 25, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60458083 |
Mar 26, 2003 |
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Current U.S.
Class: |
424/489 |
Current CPC
Class: |
A61K 9/0075 20130101;
A61K 9/14 20130101 |
Class at
Publication: |
424/489 |
International
Class: |
A61K 009/58; A61K
009/14 |
Claims
What is claimed is:
1. A process for preparing an active pharmaceutical ingredient
having a specific surface area of at least about 5.0 m.sup.2/g as
measured by B.E.T. comprising: a) storing the active pharmaceutical
ingredient at a temperature of below about 0.degree. C.; and b)
micronizing the active pharmaceutical ingredient to obtain a
specific surface area of at least about 5.0 m.sup.2/g.
2. The process of claim 1, wherein the storing is carried out at a
temperature of about -10.degree. C. to about -20.degree. C.
3. The process of claim 1, wherein the storing is carried out for
at least about 4 hours.
4. The process of claim 3, wherein the storing is carried out for
at least about 24 hours.
5. The process of claim 1, further comprising the step of storing
the micronized active pharmaceutical ingredient at a temperature of
below about -10.degree. C.
6. The process of claim 5, wherein the temperature is of about
-10.degree. C. and -20.degree. C.
7. The process of claim 5, wherein the storing is carried out for
at least about 4 hours.
8. The process of claim 7, wherein the storing is carried out for
at least about 24 hours.
9. The process of claim 5, further comprising re-micronizing.
10. The process of claim 9, wherein the re-micronizing yields an
active pharmaceutical ingredient having S.S.A. of about 6.0
m.sup.2/g to about 7.0 m.sup.2/g, as measured by B.E.T.
11. The process of claim 1, wherein mironization is carried out
with a feed rate of about 4 kg/hr to about 30 kg/hr.
12. The process of claim 11, wherein the feed rate is about 20
kg/hr.
13. The process of claim 1, wherein mironizing is carried out with
a feed air pressure of about 2 bar to about 10 bar.
14. The process of claim 13, wherein the feed air pressure is of
about 8 bar to about 8.5 bar.
15. The process of claim 1, further comprising re-micronizing.
16. The process of claim 15, wherein the re-micrinizing yields and
active pharmaceutical ingredient having a specific surface area of
about 6.0 m.sup.2/g to about 7.0 m.sup.2/g, as measured by
B.E.T.
17. The process of claim 1, wherein the active pharmaceutical
ingredient has low bioavailability or is formulated for extended
release.
18. The process of claim 17, wherein the active pharmaceutical
ingredient is selected from the group consisting of nifedipine and
leuprolide.
19. The process of claim 18, wherein the active pharmaceutical
ingredient is nifedipine.
20. The process of claim 18, wherein the process results in
nifedipine with a specific surface area of at least about 5.5
m.sup.2/g.
21. The process of claim 1, wherein the active pharmaceutical
ingredient is administered by inhalation.
22. The process of claim 21, wherein the active pharmaceutical
ingredient is salmeterol.
23. A process for preparing nifedipine having a specific surface
area of at least about 5.0 m.sup.2/g as measured by B.E.T.
comprising: a) storing nifedipine powder for a first time at a
temperature below about 0.degree. C. for at least about 4 hours; b)
micronizing the nifedipine for a first time to obtain a specific
surface area of about 5.0 m.sup.2/g to about 6.0 m.sup.2/g, as
measured by B.E.T.; c) storing the nifedipine for a second time at
a temperature below about -10.degree. C.; and d) micronizing the
nifedipine of step c for a second time to obtain an specific
surface area of about 6.0 m.sup.2/g to about 7.0 m.sup.2/g, as
measured by B.E.T.
24. The process of claim 23, wherein the storing is carried out at
a temperature of about -10.degree. C. to about -20.degree. C.
25. The process of claim 23, wherein the storing is carried out for
at least about 24 hours.
26. The process of claim 23, wherein mironization is carried out
with a feed rate of about 4 kg/hr to about 30 kg/hr.
27. The process of claim 26, wherein the feed rate is about 20
kg/hr.
28. The process of claim 23, wherein mironizing is carried out with
a feed air pressure of about 2 bar to about 10 bar.
29. The process of claim 28, wherein the feed air pressure is of
about 8 bar to about 8.5 bar.
30. A process for maintaining specific surface area of an active
pharmaceutical ingredient having a specific surface area of at
least about 5.0 m.sup.2/g as measured by B.E.T. comprising the step
of storing the active pharmaceutical ingredient at a temperature of
below about -10.degree. C., wherein the active pharmaceuticcal
ingredient retains a specific surface area within about 0.5
m.sup.2/g after at least about six months, as measured by
B.E.T.
31. The process of claim 30, wherein the active pharmaceutical
ingredient is selected from the group consisting of nifedipine,
leuprolide and salmeterol.
32. The process of claim 30, wherein the storing is carried out at
a temperature of between about -10.degree. C. and about -20.degree.
C.
33. The process of claim 30, wherein the storing is carried out for
at least about 24 hours.
34. The process of claim 30, wherein mironization is carried out
with a feed rate of about 4 kg/hr to about 30 kg/hr.
35. The process of claim 34, wherein the feed rate is about 20
kg/hr.
36. The process of claim 30, wherein mironizing is carried out with
a feed air pressure of about 2 bar to about 10 bar.
37. The process of claim 36, wherein the feed air pressure is of
about 8 bar to about 8.5 bar.
38. A process for preparing a pharmaceutical oral dosage form
comprising: a) storing an active pharmaceutical ingredient having a
particle size distribution of about 15 to about 30 icrons for a
first time at a temperature of below about 0.degree. C. for at
least about 4 hours; b) micronizing the stored active
pharmaceutical ingredient for a first time to obtain an S.S.A. of
at least about 5.5 m.sup.2/g, as measured by B.E.T.; c) storing the
active pharmaceutical ingredient for a second time at a temperature
of below about -10.degree. C.; d) micronizing the active
pharmaceutical ingredient for a second time to obtain a specific
surface area of at least about 6.5 m.sup.2/g, as measured by
B.E.T.; e) storing the active pharmaceutical ingredient at a
temperature of below about -10.degree. C. for a second time; and f)
converting the active pharmaceutical ingredient to a pharmaceutical
oral dosage form.
39. The process of claim 38, wherein the active pharmaceutical
ingredient is selected from the group consisting of nifedipine,
leuprolide and salmeterol.
40. The process of claim 38, wherein the storing is carried out at
a temperature of between about -10.degree. C. and about -20.degree.
C.
41. The process of claim 38, wherein the storing is carried out for
at least about 24 hours.
42. The process of claim 38, wherein mironization is carried out
with a feed rate of about 4 kg/hr to about 30 kg/hr.
43. The process of claim 42, wherein the feed rate is about 20
kg/hr.
44. The process of claim 38, wherein mironizing is carried out with
a feed air pressure of about 2 bar to about 10 bar.
45. The process of claim 44, wherein the feed air pressure is of
about 8 bar to about 8.5 bar.
46. A process for preparing an active pharmaceutical ingredient
selected from the group consisting of nifedipine, salmeterol and
leuprolide, having a specific surface area of at least about 5.5
m.sup.2/g as measured by B.E.T. comprising: a) storing the active
pharmaceutical ingredient at a temperature of below about 0.degree.
C. for at least about 4 hours; and b) micronizing the stored active
pharmaceutical ingredient.
47. The process of claim 46, wherein the active pharmaceutical
ingredient is nifedipine.
48. The process of claim 47, wherein micronization is carried out
with a feed rate of about 4 kg/hr to about 30 kg/hr and a feed air
pressure of about 2 bar to about 10 bar.
49. The process of claim 48, wherein the feed rate is about 20
kg/hr and the feed air pressure is of about 8 bar to about 8.5
bar.
50. The process of claim 48, further comprising storing the
micronized nifedipine at a temperature of below about -10.degree.
C.
51. The process of claim 50, further comprising converting the
obtained nifdipine into formulation.
52. A process for preparing an active pharmaceutical ingredient
comprising: a) storing the active pharmaceutical ingredient at a
temperature of below about 0.degree. C. for at least about 24
hours; and b) micronizing the active pharmaceutical ingredient,
wherein the storing results in a minimum increase of about 0.5/g2
in specific surface area compared to micronizing without
storing.
53. The process of claim 52, wherein the temperature is of about
-10 to about -20.degree. C.
54. A process for preparing a pharmaceutical oral dosage form
comprising: a) storing an active pharmaceutical ingredient for a
first time at a temperature of below about negative 10.degree. C.
for at least about 24 hours; b) micronizing the stored active
pharmaceutical ingredient at a feed rate of about 20 kg/hr and a
feed air pressure of about 8 bar to about 8.5 bar for a first time
to obtain an S.S.A. of at least about 5.5 m.sup.2/g, as measured by
B.E.T.; c) storing the active pharmaceutical ingredient for a
second time at a temperature of below about -10.degree. C.; d)
micronizing the stored active pharmaceutical ingredient for a
second time at a feed rate of about 20 kg/hr and a feed air
pressure of about 8 bar to about 8.5 bar to obtain an S.S.A. of at
least about 6.5 m.sup.2/g, as measured by B.E.T.; e) storing the
active pharmaceutical ingredient at a temperature of below about
-10.degree. C. for a second time; and f) converting the active
pharmaceutical ingredient to a pharmaceutical oral dosage form.
Description
PRIORITY
[0001] This application claims the benefit of U.S. provisional
application Serial No. 60/458,083, filed Mar. 26, 2003, the content
of which is incorporated herein.
FIELD OF THE INVENTION
[0002] The present invention relates to the specific surface area
of active pharmaceutical ingredients.
BACKGROUND OF THE INVENTION
[0003] Formulation of an active pharmaceutical ingredient may be
problematic, particularly when the active pharmaceutical ingredient
is designed for inhalation, has low bioavailability or is used in
extended release formulations. Three active pharmaceutical
ingredients, nifedipine, salmeterol and leuprolide are used in the
present application to illustrate such problems.
[0004] Nifedipine is a calcium ion influx inhibitor (slow-channel
blocker or calcium ion antagonist) which inhibits the transmembrane
influx of calcium ions into vascular smooth muscle and cardiac
muscle. Nifedipine is prescribed for the treatment of hypertension.
Nifedipine, also known as
1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-dimethyl ester, has the
following structure: 1
[0005] and is marketed in the U.S under the tradmemarks Adalat.RTM.
and Procardia.RTM., among others. Nifedipine is disclosed and
claimed in numerous patents. For example, U.S. Pat. No. 4,412,986
is directed to a solid formulation of nifedipine having high
bioavailability and reduced bulk composed of 1 part nifedipine and
1-20 parts polyvinylpyrrolidone, methyl cellulose, hydroxypropyl
cellulose and hydroxypropylmethyl cellulose; U.S. Pat. No.
4,665,081 is directed to a dry particulate nifedipine composition
made by co-pulverization of nifedipine, casein and certain
specified inorganic excipients in absence of a liquid vehicle; U.S.
Pat. No. 4,880,623 is directed to a Solid finely divided nifedipine
composition obtained by mixing micronized nifedipine, micronized
inert excipient and a polyethylene glycol; U.S. Pat. No. 4,882,144
is directed to a solid, rapidly absorbable nifedipine composition
containing PVP, cellulose, starch, and cross-linked, insoluble
PVPP; U.S. Pat. No. 4,904,699 is directed to a liquid nifedipine
concentrate stabilized against light; U.S. Pat. No. 4,933,186 is
directed to a tablet composed of (a) a rapid release core of
nifedipine, (b) a coating having no nifedipine, and (c) a rapid
release nifedipine coating; U.S. Pat. No. 4,954,346 is directed to
a gelatin capsule filled with a liquid nifedipine composition
containing a carbonate and a surfactant; U.S. Pat. No. 4,966,772 is
directed to a delayed release nifedipine composition comprising (a)
A core containing at least 50% of nifedipine in delayed release
form, (b) A slow dissolving coating containing no nifedipine made
of a hydrophilic gel, and (c) A rapid release coating of
nifedipine; U.S. Pat. No. 5,229,116 for co-administration of
nifedipine and a flavinoid (such as that in grape juice) to prolong
bio-availability by inhibiting cytochrome P 450 oxidation; U.S.
Pat. No. 5,543,099 for granulation of inactive ingredients, such as
hydroxypropyl cellulose, with active ingredients, such as
nifedipine; followed by micronization of the granules. U.S. Publ.
No. 2003/0091626 is directed to an orally disintegrating
preparation of nifedipine. All these patents and applications are
incorporated herein by reference.
[0006] Various U.S. patents are also directed to methods of use of
nifedipine. U.S. Pat. No. 4,582,840 is directed to use of
nifedipine for combating sodium balance renal insufficiency; U.S.
Pat. No. 4,690,935 for inhibition of tumor growth, U.S. Pat. No.
4,728,660 for treatment of thromboelmbolic disease, U.S. Pat. No.
4,851,404 for treatment of sickle cell anemia, U.S. Pat. No.
4,918,076 for treatment of alcohol addiction, U.S. Pat. No.
4,978,533 for treatment of coronary insufficiency, U.S. Pat. No.
5,053,419 for treatment of AIDS dimentia complex, U.S. Pat. No.
5,071,642 for use of claimed formulation to treat coronary heart
disease or high blood pressure, U.S. Pat. No. 5,124,340 for
treatment for cocaine addiction, U.S. Pat. No. 5,145,859 for
treatment of interstitial cystitis and urethral syndrome. All these
patents are incorporated herein by reference.
[0007] Nifedipine is a yellow crystalline substance, soluble in
acetone, but practically insoluble in water. The lack of solubility
of nifedipine creates a problem since bioavailability of a water
insoluble active ingredient is usually poor. An approach to
increasing bioavailability of an active pharmaceutical ingredient
is through manipultation of specific surface area. Nifedipine, as
well as other active pharmaceutical ingredients, may possess a
certain Specific Surface Area (S.S.A.), which may affect their
bioavailability. (See generally Lantz, Russel J.Jr, size reduction,
in Lachman Leon & Lieberman Herbert A. Pharmaceutical dose
forms Vol. 2, p. 77-152, incorporated herein by reference)
(Hereinafter "Lantz").
[0008] Nifedipine with specific surface area is disclosed and
claimed in U.S. Pat. No. 5,264,446. U.S. Pat. No. 5,264,446 is
directed to a sustained release formulation comprising nifedipine
crystals having a specific surface area of 1.0-4 m.sup.2/g. The
'446 patent is incorporated herein by reference. Nifedipine with a
high surface area has also been subject of litigation in the United
States. See Bayer A G v. Biovail Co., 279 F.3d 1340 (Fed. Cir.
2002).
[0009] Another active pharmaceutical ingredient is salmeterol,
disclosed in U.S. Pat. No. 4,992,474, and marketed under the name
SERVENT and ADVAIR as a xinofoate salt. According to the maker of
SERVENT, salmeterol xinafoate is a white to off-white powder that
is freely soluble in methanol; slightly soluble in ethanol,
chloroform, and isopropanol; and sparingly soluble in water.
Salmetero xinafoate has the following structure: 2
[0010] Salmetero xinofoate is a bronchodilator for treatment of
obstructive lung conditions such as asthma, emphysema and chronic
brochitis. It is administrated as a powder for inhalation. The
inhalable particle should be in size of less than 3 icrons for
absorption. Micronization of salmeterol xinofoate by traditional
methods and their adverse effects are discussed in Shekunov. B. Y.
et al "Physical properties of supercritically-processed and
micronised powders for respiratory drug delivery" in KONA No. 20,
2002, incorporated herein by reference.
[0011] Another pharmaceutical active ingredient is leuprolide,
which is marketed under the name LUPRON as an acetate salt.
According to the maker of LUPRON, leupromide is an injectable
synthetic nonapeptide analog of naturally occurring gonadotropin
releasing hormone (GnRH or LH-RH) and has the chemical name
5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-ty-
rosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate
(salt). Micronization, by increasing solubility, makes injectables
APIs more suitable. Also peptides may be used for systemic
inhalation therapy. In order to obtain good absorption of the the
active pharmaceutical ingredient in the lungs, the active
pharmaceutical ingredient should be micronized to size smaller than
3 icrons. Conventional micronization may not be efficient and might
damage the active pharmaceutical ingredient.
[0012] Specific Surface area is defined in units of square meters
per gram (m.sup.2/g). It is usually measured by nitrogen absorption
analysis (See Lantz). In this analysis, nitrogen is absorbed on the
surface of the substance. The amount of the absorbed nitrogen (as
measured during the absorption or the subsequent desorption
process) is related to the surface area via a formula known as the
B.E.T. formula. An instrument by Strohlein (for example model
areameter 2) is mentioned during prosecution of U.S. Pat. No.
5,264,446. Other commercial instrument are manufactured by
quantachrome (for example model monosorb) or Coulter (for example
model SA3100. ) The analysis may be performed in a single test
(single point measurement) or in a series of tests in various
nitrogen pressures (multipoint measurement).
[0013] S.S.A. of an active pharmaceutical ingredient may be
affected by various factors. There is a general connection between
Specific Surface Area and Particle Size Distribution (P.S.D.); the
smaller the Particle Size Distribution, the higher the Specific
Surface Area. Additional factors affecting S.S.A. are the particle
shape, the particle porosity, and inter-particle binding forces
known to create aggregation or agglomeration. The following table,
based on experiments performed by the applicants, describes the
relation between the S.S.A. and the mean P.S.D., d(0.5) of
nifedipine:
[0014] It has been shown that nifedipine with a high surface area
has greater bioavailability. See e.g. U.S. Pat. No. 5,264,446.
According to the seventh edition of Pharmaceutical Dosage Forms and
Drug Delivery Systems, other active pharmaceutical ingredients that
show greater bioavailability upon micronization include
theophylline, griseofluvin, sulfisoxazole and nitrofurantoin. There
is a need in the art to prepare active pharmaceutical ingredients
such as nifedipine with a high surface area to obtain formulations
with greater bioavalability, and to compensate for any loss of
surface area before formulation. Micronizaton also helps in
absorption of inhaled active pharmaceutical ingredients.
[0015] Micronization also allows for formulation of such active
ingredients for extended release. For example, when an active
pharmaceutical ingredient is used in extended release formulations,
it is possible with the process of the present invention to put the
API on a plurality of pellets, with some pellets containing
micronized API, while others non-micornized API. See e.g. Ansel et
al, Pharmaceutical Dosage Forms And Drug Delivery Systems, 7.sup.th
ed. Page 232. It is also possible to use a hydrogel, such as with
HPMC, containing micronized and non-micronized particles, where the
micronized particles escape the hydrogel at a faster rate. In some
situations, only micronized particles may be used with a hydrogel,
where non-micronized particles would be too large to escape the
hydrogel effectively over time. There is a need in the art for
effective micronization of pharmaceutical active ingredients.
SUMMARY OF THE INVENTION
[0016] In one aspect, the present invention provides a process for
preparing an active pharmaceutical ingredient having a specific
surface area of at least about 5.0 m.sup.2/g as measured by B.E.T.
comprising storing the active pharmaceutical ingredient at a
temperature of below about 0.degree. C. and micronizing the active
pharmaceutical ingredient to obtain a specific surface area of at
least about 5.0 m.sup.2/g.
[0017] In another aspect, the present invention provides a process
for preparing nifedipine having a specific surface area of at least
about 5.0 m.sup.2/g as measured by B.E.T. comprising storing
nifedipine powder for a first time at a temperature below about
0.degree. C. for at least about 4 hours, micronizing the nifedipine
for a first time to obtain a specific surface area of about 5.0
m.sup.2/g to about 6.0 m.sup.2/g, as measured by B.E.T., storing
the nifedipine for a second time at a temperature below about
-10.degree. C. and micronizing the nifedipine of step c for a
second time to obtain an specific surface area of about 6.0
m.sup.2/g to about 7.0 m.sup.2/g, as measured by B.E.T.
[0018] In another aspect, the present invention provides a process
for maintaining specific surface area of an active pharmaceutical
ingredient having a specific surface area of at least about 5.0
m.sup.2/g as measured by B.E.T. comprising the step of storing the
active pharmaceutical ingredient at a temperature of below about
-10.degree. C., wherein the active pharmaceuticcal ingredient
retains a specific surface area within about 0.5 m.sup.2/g after at
least about six months, as measured by B.E.T.
[0019] In another aspect, the present invention provides a process
for preparing a pharmaceutical oral dosage form comprising storing
an active pharmaceutical ingredient having a particle size
distribution of about 15 to about 30 icrons for a first time at a
temperature of below about 0.degree. C. for at least about 4 hours,
micronizing the stored active pharmaceutical ingredient for a first
time to obtain an S.S.A. of at least about 5.5 m.sup.2/g, as
measured by B.E.T., storing the active pharmaceutical ingredient
for a second time at a temperature of below about -10.degree. C.,
micronizing the active pharmaceutical ingredient for a second time
to obtain a specific surface area of at least about 6.5 m.sup.2/g,
as measured by B.E.T., storing the active pharmaceutical ingredient
at a temperature of below about -10.degree. C. for a second time
and converting the active pharmaceutical ingredient to a
pharmaceutical oral dosage form.
[0020] In another aspect, the present invention provides a process
for preparing an active pharmaceutical ingredient selected from the
group consisting of nifedipine, salmeterol and leuprolide, having a
specific surface area of at least about 5.5 m.sup.2/g as measured
by B.E.T. comprising storing the active pharmaceutical ingredient
at a temperature of below about 0.degree. C. for at least about 4
hours and micronizing the stored active pharmaceutical
ingredient.
[0021] In another aspct, the present invention provides a process
for preparing an active pharmaceutical ingredient comprising
storing the active pharmaceutical ingredient at a temperature of
below about 0.degree. C. for at least about 24 hours and
micronizing the active pharmaceutical ingredient, wherein the
storing results in a minimum increase of about 0.5 m/g2 in specific
surface area compared to micronizing without storing (such as
storage at room temperature).
[0022] In another aspect, the present invention provides a process
for preparing a pharmaceutical oral dosage form comprising storing
an active pharmaceutical ingredient for a first time at a
temperature of below about negative 10.degree. C. for at least
about 24 hours, micronizing the stored active pharmaceutical
ingredient at a feed rate of about 20 kg/hr and a feed air pressure
of about 8 bar to about 8.5 bar for a first time to obtain an
S.S.A. of at least about 5.5 m.sup.2/g, as measured by B.E.T.,
storing the active pharmaceutical ingredient for a second time at a
temperature of below about -10.degree. C., micronizing the stored
active pharmaceutical ingredient for a second time at a feed rate
of about 20 kg/hr and a feed air pressure of about 8 bar to about
8.5 bar to obtain an S.S.A. of at least about 6.5 m.sup.2/g, as
measured by B.E.T., storing the active pharmaceutical ingredient at
a temperature of below about -10.degree. C. for a second time and
converting the active pharmaceutical ingredient to a pharmaceutical
oral dosage form.
DETAILED DESCRIPTION OF THE INVENTION
[0023] As used herein, the term "micronization" refers to a
decrease in particle size through application of force to a
particle, resulting in the break-up of the particle. Such force may
be applied by collision of particles at high speeds.
[0024] The present invention provides a process for preparing an
active pharmaceutical ingredient, particularly those that are used
for inhalation, have low bioavailability and are used in extended
release formulations, with a high surface area, i.e., at least
about 4.0 m.sup.2/g. Preferably, the active pharmaceutical
ingredient of the present invention has an S.S.A. of more than
about 5.0 m.sup.2/g, more preferably, more than about 5.5
m.sup.2/g, and most preferably, more than about 6.5 m.sup.2/g. In
one embodiment, the S.S.A. is from about 5.0 m.sup.2/g to about 7.0
m.sup.2/g, more preferably from about 6.0 m.sup.2/g to about 7.0
m.sup.2/g.
[0025] The term active pharmaceutical ingredient (API) in the
present invention encompasses small organic molecules and peptides,
their salts and esters, and refers to the ingredient having
physiological activity after administration to a mammal. Adjuvants
(when a secondary active pharmaceutical ingredient is administered)
are included within the term active pharmaceutical ingredient.
Preferred API include nifedipine, leuprolide and salmeterol, with
nifedipine being most preferred.
[0026] In the process of the present invention, an active
pharmaceutical ingredient is stored at a temperature of below
0.degree. C., preferably below about -10.degree. C., most
preferably of about -10.degree. C. and about -20.degree. C. for a
sufficient time to allow for increasing the specific surface area
upon micronization. Preferably the storage is carried out for such
time that an increase of 0.5 m.sup.2/g over micronization without
storage is obtained. Storage is preferably carried out until the
API reaches the temperture of the freezer, preferably for at least
about 4 hours, more preferably for at least about 24 hours. The
storage could for example be for about a day, about 2-3 days, about
a week, or about a month. The cooled API is then micronized within
a reasonable time after being taken out of the freezer, preferably
with an immediate intial feed, such as in less than about 30
minutes, more preferably in less than about 15 minutes, and most
preferably in less than about 1-5 minutes, so that a substantial
loss in temperature of the API does not occur before
micronization.
[0027] After micronization, the micronized API is preferably kept
at a temperature of below about -10.degree. C. to maintain the
obtained surface area. More preferably, the API is stored at a
temperature of between about -10.degree. C. and about -20.degree.
C.
[0028] Micronization and storage at such temperature may further
protect the API against chemical and/or physical degradation.
[0029] The feed rate for micronization is preferably of about 4
kg/hr to about 30 kg/hr, most preferably, the feed rate is about 20
kg/hr. The feed air pressure is preferably of about 2 bar to about
10 bar, most preferably the feed air pressure is of about 8 bar to
about 8.5 bar.
[0030] Preferably, the API micronized is a powder in the solid
state and may be in the form of crystals, powder aggregates and
course powder, preferably as a fine powder of crystals with
particle size distribution of about 10 to about 40 icrons, more
preferably about 15 to about 30 icrons. The starting API may have a
surface area as low as from about 0.5 m.sup.2/g to about 1
m.sup.2/g.
[0031] The micronization step preferably decreases the size of the
stored API to less than about 3.mu., preferably to less than about
1.mu., and preferably increases the stored API surface area to at
least about 5.5 m.sup.2/g.
[0032] Preferably, the micronization is performed with a
fluid-energy mill. One of skill in the art appreciates that a fluid
energy mill, or micronizer, is an especially preferred type of mill
for its ability to produce particles of small size in a narrow size
distribution. As those skilled in the art are aware, micronizers
use the kinetic energy of collision between particles suspended in
a rapidly moving fluid stream to cleave the particles. An air jet
mill is a preferred fluid energy mill. The suspended particles are
injected under pressure into a recirculating particle stream.
Smaller particles are carried aloft inside the mill and swept into
a vent connected to a powder collector,such as a cyclone or a
filter bag house.
[0033] The storage at a low temperature (below about 0.degree. C.
prferred, more preferably below about negative 10.degree. C., and
most preferably of about -10.degree. C. and about -20.degree. C.),
stabilzes the micronized nifedipine. Preferably, the storage
maintains the specific surface area in a suitable range for at
least about six months. The freezing of the micronized product
immediately after micronization stabilizes the S.S.A., which
decreases by less than about 1.0 m.sup.2/g, more preferably less
than about 0.5 m.sup.2/g in about six months. One of skill in the
art would appreciate that this rate of decrease is not applicable
after formulation since the filler would decrease contact between
various particles of the active pharmaceutical ingredient.
[0034] In order to obtain initial surface area higher than about
6.5 m.sup.2/g, the micronization process is preferably repeated.
Re-micronization may be also used to regenerate a decreased surface
area. For example, a substance with initial S.S.A. of about 5.5
m.sup.2/g, which decreases with time to about 5.0 m.sup.2/g, may
re-gain an S.S.A. of about 6.5 m.sup.2/g after passing the above
process (freezing, micronization, re-freezing). It is possible to
re-micronize immdiately without further freezing as long as the
active pharmaceutical ingredient is at a sufficiently low
temperature.
[0035] Further steps such as packaging, transportation and
long-term storage are preferably performed in temperatures of below
about 8.degree. C., more preferably, at below about -10.degree. C.,
and most preferably of about -10.degree. C. to about -20.degree. C.
If all the steps are performed in a temperature of below about
-10.degree. C., the API's S.S.A. or that of another active
pharmaceutical ingredient may not decrease by more than about 1
m.sup.2/g, more preferably 0.5 m.sup.2/g in at least about three
months, and most preferably in at least about six months.
[0036] The pharmaceutical compositions of the present invention,
such as oral and inhaled phamaceutical dosage forms, contain
nifedipine, leuprolide, salmeterol, theophylline, griseofluvin,
sulfisoxazole and nitrofurantoin with a high surface area,
optionally in a mixture with other active ingredients. In addition
to the active ingredient(s), the pharmaceutical compositions of the
present invention may contain one or more excipients. Excipients
are added to the composition for a variety of purposes.
[0037] Diluents increase the bulk of a solid pharmaceutical
composition, and may make a pharmaceutical dosage form containing
the composition easier for the patient and care giver to handle.
Diluents for solid compositions include, for example,
microcrystalline cellulose (e.g. Avicel.RTM.), microfine cellulose,
lactose, starch, pregelitinized starch, calcium carbonate, calcium
sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium
phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium
carbonate, magnesium oxide, maltodextrin, mannitol,
polymethacrylates (e.g. Eudragit.RTM.), potassium chloride,
powdered cellulose, sodium chloride, sorbitol and talc.
[0038] Solid pharmaceutical compositions that are compacted into a
dosage form, such as a tablet, may include excipients whose
functions include helping to bind the active ingredient and other
excipients together after compression. Binders for solid
pharmaceutical compositions include acacia, alginic acid, carbomer
(e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl
cellulose, gelatin, guar gum, hydrogenated vegetable oil,
hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel.RTM.),
hydroxypropyl methyl cellulose (e.g. Methocel.RTM.), liquid
glucose, magnesium aluminum silicate, maltodextrin,
methylcellulose, polymethacrylates, povidone (e.g. Kollidon.RTM.,
Plasdone.RTM.), pregelatinized starch, sodium alginate and
starch.
[0039] The dissolution rate of a compacted solid pharmaceutical
composition in the patient's stomach may be increased by the
addition of a disintegrant to the composition. Disintegrants
include alginic acid, carboxymethylcellulose calcium,
carboxymethylcellulose sodium (e.g. Ac-Di-Sol.RTM.,
Primellose.RTM.), colloidal silicon dioxide, croscarmellose sodium,
crospovidone (e.g. Kollidon.RTM., Polyplasdone.RTM.), guar gum,
magnesium aluminum silicate, methyl cellulose, microcrystalline
cellulose, polacrilin potassium, powdered cellulose, pregelatinized
starch, sodium alginate, sodium starch glycolate (e.g.
Explotab.RTM.) and starch.
[0040] Glidants can be added to improve the flowability of a
non-compacted solid composition and to improve the accuracy of
dosing. Excipients that may function as glidants include colloidal
silicon dixoide, magnesium trisilicate, powdered cellulose, starch,
talc and tribasic calcium phosphate.
[0041] When a dosage form such as a tablet is made by the
compaction of a powdered composition, the composition is subjected
to pressure from a punch and dye. Some excipients and active
ingredients have a tendency to adhere to the surfaces of the punch
and dye, which can cause the product to have pitting and other
surface irregularities. A lubricant can be added to the composition
to reduce adhesion and ease the release of the product from the
dye. Lubricants include magnesium stearate, calcium stearate,
glyceryl monostearate, glyceryl palmitostearate, hydrogenated
castor oil, hydrogenated vegetable oil, mineral oil, polyethylene
glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl
fumarate, stearic acid, talc and zinc stearate.
[0042] Flavoring agents and flavor enhancers make the dosage form
more palatable to the patient. Common flavoring agents and flavor
enhancers for pharmaceutical products that may be included in the
composition of the present invention include maltol, vanillin,
ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol,
and tartaric acid.
[0043] Solid and liquid compositions may also be dyed using any
pharmaceutically acceptable colorant to improve their appearance
and/or facilitate patient identification of the product and unit
dosage level.
[0044] In liquid pharmaceutical compositions of the present
invention, the active pharmaceutical ingredient and any other solid
excipients are dissolved or suspended in a liquid carrier such as
water, vegetable oil, alcohol, polyethylene glycol, propylene
glycol or glycerin.
[0045] Liquid pharmaceutical compositions may contain emulsifying
agents to disperse uniformly throughout the composition an active
ingredient or other excipient that is not soluble in the liquid
carrier. Emulsifying agents that may be useful in liquid
compositions of the present invention include, for example,
gelatin, egg yolk, casein, cholesterol, acacia, tragacanth,
chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol
and cetyl alcohol.
[0046] Liquid pharmaceutical compositions of the present invention
may also contain a viscosity enhancing agent to improve the
mouth-feel of the product and/or coat the lining of the
gastrointestinal tract. Such agents include acacia, alginic acid
bentonite, carbomer, carboxymethylcellulose calcium or sodium,
cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar
gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl
methyl cellulose, maltodextrin, polyvinyl alcohol, povidone,
propylene carbonate, propylene glycol alginate, sodium alginate,
sodium starch glycolate, starch tragacanth and xanthan gum.
[0047] Sweetening agents such as sorbitol, saccharin, sodium
saccharin, sucrose, aspartame, fructose, mannitol and invert sugar
may be added to improve the taste.
[0048] Preservatives and chelating agents such as alcohol, sodium
benzoate, butylated hydroxy toluene, butylated hydroxyanisole and
ethylenediamine tetraacetic acid may be added at levels safe for
ingestion to improve storage stability.
[0049] According to the present invention, a liquid composition may
also contain a buffer such as guconic acid, lactic acid, citric
acid or acetic acid, sodium guconate, sodium lactate, sodium
citrate or sodium acetate.
[0050] Selection of excipients and the amounts used may be readily
determined by the formulation scientist based upon experience and
consideration of standard procedures and reference works in the
field.
[0051] The solid compositions of the present invention include
powders, granulates, aggregates and compacted compositions. The
dosages include dosages suitable for oral, buccal, rectal,
parenteral (including subcutaneous, intramuscular, and
intravenous), inhalant and ophthalmic administration. Although the
most suitable administration in any given case will depend on the
nature and severity of the condition being treated, the most
preferred route of the present invention is oral. The dosages may
be conveniently presented in unit dosage form and prepared by any
of the methods well-known in the pharmaceutical arts.
[0052] Dosage forms include solid dosage forms like tablets,
powders, capsules, suppositories, sachets, troches and losenges, as
well as liquid syrups, suspensions and elixirs.
[0053] The dosage form of the present invention may be a capsule
containing the composition, preferably a powdered or granulated
solid composition of the invention, within either a hard or soft
shell. The shell may be made from gelatin and optionally contain a
plasticizer such as glycerin and sorbitol, and an opacifying agent
or colorant.
[0054] The active ingredient and excipients may be formulated into
compositions and dosage forms according to methods known in the
art.
[0055] A composition for tableting or capsule filling may be
prepared by wet granulation. In wet granulation, some or all of the
active ingredients and excipients in powder form are blended and
then further mixed in the presence of a liquid, typically water,
that causes the powders to clump into granules. The granulate is
screened and/or milled, dried and then screened and/or milled to
the desired particle size. The granulate may then be tableted, or
other excipients may be added prior to tableting, such as a glidant
and/or a lubricant.
[0056] A tableting composition may be prepared conventionally by
dry blending. For example, the blended composition of the actives
and excipients may be compacted into a slug or a sheet and then
comminuted into compacted granules. The compacted granules may
subsequently be compressed into a tablet.
[0057] As an alternative to dry granulation, a blended composition
may be compressed directly into a compacted dosage form using
direct compression techniques. Excipients that are particularly
well suited for direct compression tableting include
microcrystalline cellulose, spray dried lactose, dicalcium
phosphate dihydrate and colloidal silica. The proper use of these
and other excipients in direct compression tableting is known to
those in the art with experience and skill in particular
formulation challenges of direct compression tableting.
[0058] A capsule filling of the present invention may comprise any
of the aforementioned blends and granulates that were described
with reference to tableting, however, they are not subjected to a
final tableting step.
[0059] In one embodiment, the capsules, tablets and lozenges, and
other unit dosage forms preferably contain about 10 to about 90 g
of nifedipine. The capsules preferably contain from about 10 g to
about 20 g of nifedipine, while the tablets, preferably in the form
of extended release, contain from about 30 g to about 90 g of
nifedipine. A preferred host is a mammal, most preferably a
human.
[0060] Nifedipine may be administered alone or in combination with
other hypertensive agents. Preferably nifedipine is administered in
a maintenance dose of from about 30 g to about 60 g per day, once a
day on an empty stomach.
[0061] The formulations of the present invention administered via
inhalation contain powder administered by the help of dry-powder
inhalers. In addition to the API, these inhaled compositions
include inert propelants, and pharmaceutical diluents, such as
alpha lactose monohydrate, to aid the formulations flow properties,
metering uniformity and to protect the powder agaist effects of
humidity (Ansel et al, pg 172). A particularly favored formulation
is a diskus containing about 100/50 mcg, 250/50 mcg or 500/50 mcg
of fluticasone and salmeterol xinofoate (base equivalent).
Salmeterol xinofoate administered is preferably microfine and
contains a sugar such as lactose for formulation.
EXAMPLES
[0062] Instrumentation:
[0063] Freezer with controlled temperature at -10.degree. C. to
-20.degree. C.
[0064] Micronizer: Fluid energy mill such as Microgrinding MC-500
KX, Hosokawa Fluidized bed opposed jet mill AFG.RTM., Sturtavent
micronizer jet mill.
Example 1
[0065] This example illustrates a process for obtaining an API with
initial S.S.A. of at least about 5.5 m.sup.2/g:
[0066] A sample of nifedipine with an average particle size
ditribution of about 20-30 icrons was put in a freezer at a
temperature of about -10.degree. C. to about -20.degree. C. for
about 24 hours to become embrittled. The resulting API was then put
in a micronizer, and micronized at a controlled feed rate and air
pressure. For the microgrinding, the feed rate was 20.+-.1 kg/hr,
the feed air pressure was 8-8.5 bar and the grinding air was 3-4.5
bar.
[0067] The micronized product was immediately transferred back into
the freezer. (A package of 10 Kg was used, once the package was
full, the package was sealed and transferred to the freezer. Since
the feed rate in this example was about 20 Kg/hr, the API went into
the freezer within about 30 minutes of micronization.)
Example 2
[0068] This example illustrates a process for obtaining API with
initial S.S.A. of at least about 6.5 m.sup.2/g:
[0069] The process was the same as that illustrated in Example 1,
but the micronization process was repeated twice under the same
micronization parameters, with the subsequent freezing, to obtain
nifedipine with an S.S.A. of at least about 6.5 m.sup.2/g.
Example 3
[0070] PROPHETIC-This example illustrates a process for
re-generating S.S.A. of at least 5.5 m.sup.2/g:
[0071] A nifedipine sample whose S.S.A. has decreased is used as a
starting API in the process of either examples 1 or 2 to regain or
exceed its original S.S.A.
Example 4
Comparative Example
[0072] Nifedipine with the same characteristics as example 1 was
micronized under the same conditions without being put in a
freezer. The result was a nifedipine with an S.S.A. of 4.6
m.sup.2/g.
Example 5
[0073] PROPHETIC
[0074] An active pharmaceutical ingrdient is kept in temperature
-10 to -20.degree. C. It is micronized with a micronizer such as
microgrinding MC-100 with feed rate of 0.2 kg/hr, feed air pressure
of 8 bar and grinding air pressure of 6 bar. The API is stored at
-10 to -20.degree. C. after micronization to preserve it from
losing its surface properties by mechanisms such as
amorphization.
Example 6
[0075] PROPHETIC
[0076] An active pharmaceutical ingredient is kept at a temperature
of -10 to -20.degree. C. It is micronized with a micronizer such as
microgrinding MC-100 with feed rate of 0.2 kg/hr, feed air pressure
of 8 bar and grinding air pressure of 6 bar. The API is stored at
-10 to -20.degree. C. after micronization to preserve its surface
properties.
[0077] Having thus described the invention with reference to
particular preferred embodiments and illustrative examples, those
in the art can appreciate modifications to the invention as
described and illustrated that do not depart from the spirit and
scope of the invention as disclosed in the specification. The
Examples are set forth to aid in understanding the invention but
are not intended to, and should not be construed to, limit its
scope in any way. The examples do not include detailed descriptions
of conventional methods. Such methods are well known to those of
ordinary skill in the art and are described in numerous
publications. All references mentioned herein are incorporated in
their entirety.
* * * * *